B12 and Folate Deficiencies

Question 1

What are haematinics and give 3 examples

Answer 1

• The vitamins required to make blood

1. Vit B12
2. Folate
3. Iron

Question 2

B12 is required for both ….. ….. and ….. ….. ….. ….. …..

(overall functions)

Answer 2

B12 is required for both DNA synthesis and integrity of the nervous system

Question 3

Folic acid is required for both ….. ….. and ….. …..

Answer 3

Folic acid is required for both DNA synthesis and homocysteine metabolism

Question 4

Outline the role of B12 and folate in DNA synthesis - in the biosynthetic pathway (but like basic detail don’t need to go through the whole complete pathway just their roles they play)

Answer 4

• DNA synthesis requires deoxythymidine precursor
• Deoxythmidine is formed from methylation of deoxyuridine
• Dietary folate is converted to something else in a multi-step process which carries out this methylation of deoxyuridine - so folate is required to methylate deoxyuridine into deoxythymidine to form DNA
• B12 is a cofactor in the process. It is required in order to convert dietary folate into the final chemical form in which it can carry out the methylation of deoxyuridine. So B12 is a cofactor to convert dietary folate into another active form such that it can methylate deoxyuridine into deoxythymidine in order to synthesise DNA

Question 5

What are the clinical features of B12 / folate deficiency?

Answer 5

ANAEMIA

• Weakness, tiredness, SOB
• Jaundice due to cell breakdown in this anaemia

GI EFFECTS

• Glossitis
• Angular cheilosis (inflammation at ends of lips (where top and bottom meet at edges - angled)
• Weight loss
• Change of bowel habit

OTHER

• Sterility may occur

Question 6

What type of anaemia does B12 / folate deficiency result in?

Answer 6

Macrocytic, megaloblastic anaemia

Question 7

Give 5 causes of macrocytic anaemia - last one is haematological disorders, give 3 examples for this one

Answer 7

1. Vitamin B12 / folate deficiency
2. Liver disease / alcohol
3. Hypothyroidism - causes macrocytic but not megaloblastic anaemia
4. Drugs e.g. azathioprine
5. Haematological disorders - myelodysplasia, aplastic anaemia, reticulocytosis (chronic haemolytic anaemia)

Question 8

Outline normal red cell maturation stages (after HSC then BFU-E) and qualitatively describe the changes seen in the nucleus and cytoplasm

Answer 8

• PROERYTHROBLAST → ERYTHROBLAST → NORMOBLAST (early/intermediate/late) → RETICULOCYTE → MATURE, CIRCULATING RED CELL
• Initially very large nucleus with high nucleus:cytoplasm ratio
• This undergoes pyknosis (condenses) throughout the maturation pathway and eventually disappears in the mature red cell
• The cytoplasm appears more and more pink because of haemoglobin increasing

Question 9

What is occuring in megaloblastic anaemia / what is it?

Answer 9

• Asynchronous maturation of the nucleus and cytoplasm in the erythroid series due to abnormalities in DNA synthesis etc
• So you may see blue cytoplasm and no nucleus (early cell with no nucleus which is incorrect - you see early precursors having large nuclei in the erythroid series) and pink cytoplasm with a nucleus (pink - means lots of haemoglobin - means late in development, maybe even the mature RBC which has a nucleus which is abnormal, should be anuclear)

Question 10

What can we see in the peripheral blood films in megaloblastic anaemia?

Answer 10

• Anisocytosis
• Large red cells
• Hypersegmented neutrophils - normally only 2-5 segments but here there may be 8+
• Giant metamyelocytes
• Abnormal cells discordant with erythroid maturation series (early blue cytoplasm cells with no nuclei and late pink cytoplasm cells with nuclei)

Question 11

Where do you get dietary folate from?

Answer 11

• Leafy vegetables
• But can be destroyed by overcooking, canning, processing

Question 12

1) Give 3 examples of physiological reasons for increased folate demands
2) Give 3 examples of pathological reasons for increased folate demands

Answer 12

1)

1. Pregnancy
2. Adolescence
3. Premature babies

2)

1. Malignancy
2. Erythroderma
3. Haemolytic anaemias

Question 13

Lab diagnosis methods for folate deficiency?

Answer 13

• Serum folate
• FBC and blood film

Question 14

Give 3 consequences of folate deficiency and give examples where necessary

Answer 14

1. Megaloblastic, macrocytic anaemia
2. Neural tube defects e.g. spina bifida, anencephalophy
3. Increased CVD risk and risk of thrombosis (venous and arterial) due to high homocysteine and variant enzymes associated with homocysteine metabolism (remember folate is used in homocysteine metabolism)

Question 15

1) Give 4 neurological consequences of B12 deficiency
2) Thus how might a patient present in regards to neurological signs and symptoms?

Answer 15

1)

1. Bilateral peripheral neuropathy - so hyporeflexia
2. Subacute combined degeneration of the spinal cord (posterior and pyramidal tracts)
3. Optic atrophy
4. Dementia

2)

• Paresthesia
• Muscle weakness
• Visual impairment
• Psychiatric disturbance
• Loss of proprioception - test with Romberg’s sign (like that walking test for drunk driver type thing)
• Hyporeflexia (loss of reflexes) due to lower motor neurone impairment
• Babinkski’s sign positive due to upper motor neurone impairment

Question 16

Give 4 causes of B12 deficiency and give examples for one of these causes

Answer 16

1. POOR ABSORPTION
2. LOW DIETARY INTAKE (vegans or just poor diet)
3. INFECTION

• H. Pylori
• Giardia
• Abnormal bacterial flora
• Tropical sprue
• Fish tapeworm

4. DRUGS

• Metformin
• Proton pump inhibitors e.g. Omeprazole
• Oral contraceptive pill

Question 17

What are the 2 methods of B12 absorption and which is the major route?

Answer 17

1. B12 binds with intrinsic factor secreted by parietal cells of the stomach - this complex binds receptors in the ileum and is absorbed here (Major route - 99%)
2. Direct absorption across the duodenal wall (1% - slow and inefficient)

Question 18

B12 absorption requires what 3 things?

Answer 18

1. Intrinsic factor
2. A functioning stomach
3. A functioning small intestine

Question 19

Give 4 things that can cause impaired absorption of B12, and for one of them there are 3 sub-causes of this

Answer 19

1. Post-gastrectomy (so less parietal cells to produce intrinsic factor)
2. Gastric atrophy (so less parietal cells to produce intrinsic factor)
3. Pernicious anaemia - antibodies to intrinisic factor / parietal cells of stomach that produce intrinsic factor
4. Disease of terminal ileum due to : crohn’s, coeliac’s, surgical resection

Question 20

What is the pathophysiology of pernicious anaemia?

Answer 20

• Autoimmune
• Antibodies either directly against intrinsic factor or against the parietal cells of the stomach that produce it, thereby impairing B12 absorption by the intrinsic factor major route

Question 21

Why do males have a slightly lower life expectancy with pernicious anaemia?

Answer 21

Increased risk of stomach cancer

Question 22

If someone with B12 deficiency went on to develop iron deficiency anaemia, look out for…..

Answer 22

GI malignancy

Question 23

Describe the Shilling test - an olden test for B12

Answer 23

• Replenish B12 stores by injection until full
• Give patient radioactive sample of B12 and measure excretion in urine - normal people absorb at first but then because stores are already full they excrete again, if there’s no B12, they have B12 malabsorption for some reason
• IF no B12 in urine, test is repeated with intrinsic factor. If now resolved and B12 measured in urine, then the problem must have been due to intrinsic factor

Question 24

1) How to treat B12 deficiency?
2) How treatment differs if their is neurological involvement?

Answer 24

1)

• I/m injection
• 3 times a week for 2 weeks
• Then every 3 months

2)

• More frequent
• Alternate days until no further improvement up to 3 weeks
• Then every 2 months